Insect repellents

ABSTRACT

A number of novel carboxamides have been found to be useful insect repellents.

This is a continuation of Ser. No. 349,948, filed Feb. 18, 1982, nowabandoned, which is a continuation of application Ser. No. 240,446,filed Mar. 4, 1981, now abandoned, which in turn is a division of Ser.No. 8,814, filed Feb. 2, 1979, now U.S. Pat. No. 4,291,041, issued Sept.22, 1981.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to insect repellents and more particularly tocertain novel carboxamides containing an alicyclic moiety and their useas insect repellents.

2. Description of the Prior Art

There is a continuing need for insect repellents or formulations thereofthat are significantly more effective or longer lasting than those nowin use. All of the repellents now in use for application to the skinhave disadvantages, that is, they are not effective for long enoughperiods of time and are subject to loss by abrasion, evaporation,absorption, and immersion in water. Moreover, all cause a stingingsensation when they contact the eyelids and lips, and are effective onlywhen they are present on the skin or clothing in relatively largequantities. Mosquitoes, sand flies, black flies, stable flies, tsetseflies, gnats, and tabanids are among the many species of biting fly thatcause annoyance and distress throughout the world. Many species ofbiting insects spread human and animal diseases. There are many areasthroughout the world in both developed and developing nations where theuse of protective clothing and repellents is the only means available toindividuals for personal protection. Deet(N,N-diethyl-m-toluamide) hasproved to be the most outstanding all-purpose individual repellent yetdeveloped (Proceedings of a Symposium, University of Alberta, Edmonton,Canada, May 16-18, 1972, Defense Research Board, Ottawa, Canada, 1973.DR- 217: 109-113). Deet was reported as a promising repellent in 1954(Journal of Organic Chemistry, 19, 493, 1954). Since that time, norepellent has been reported as being superior to deet as an all-purposerepellent despite a continuing search for such a chemical.

SUMMARY OF THE INVENTION

An object of this invention is to provide a class of compounds that areuseful as insect repellents.

The above object is accomplished by a number of novel carboxamideshaving from about 11 to about 18 carbon atoms and containing analicyclic moiety. Many of these compounds are more effective thanpresently available repellents and many are effective against a widevariety of insects.

DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the formula below##STR1## wherein R³ is one of the groups A, B, or C ##STR2## R ishydrogen or lower alkyl, n is zero or the positive integer one, two, orthree, each of R¹ and R² is alkyl, or taken together represent analkylene, an alkenylene, an alkyl substituted alkylene, an alkyleneether, and alkyl substituted alkylene ether, or an alkyl substitutedalkylene amine ring structure.

The compounds of this invention are useful as insect repellents and areparticularly effective against many Dipteran.

The novel compounds of this invention are especially effective inrepelling a wide variety of insects such as ticks, chiggers,cockroaches, and biting diptera such as mosquitoes, stable flies, deerflies, black flies, and sand flies. Certain novel amides reported inthis invention are about equally as effective as deet against mosquitoesand are significantly more repellent than deet against other bitingflies when tested on skin. The skin test is the obvious critical testwhen one considers personal protection; however, clothing repellents arealso very important especially in areas of heavy mosquito infestations(The Journal of the American Medical Association, 196, 253, 1966).Certain amides of this invention provide exceptional protection againstmosquitoes when applied to cloth.

The amides were synthesized as follows: the appropriate acid chloridewas slowly added with stirring to an anhydrous ether solution of theamine cooled in an ice bath (either the amine itself or pyridine wasused as a hydrochloric acid scavenger). The reaction mixture was allowedto warm to room temperature and then allowed to stand for several hours,usually overnight. The amides were isolated by routine extractionprocedures and purified by distillation under high vacuum. Purity waschecked by gas chromatographic analysis.

A typical procedure is illustrated by the following description of thesynthesis of 1-(3-cyclohexenecarbonyl)piperidine, compound 20 in Table1: 3-cyclohexenecarbonyl chloride, 28.9 grams (0.2 mole), was addeddropwise to an ice cold solution (0°-10° C.) of piperidine, 34 grams(0.4 mole) in 250 ml of anhydrous ether. The solution was stirredvigorously during the addition. The reaction mixture was allowed to warmto room temperature and to stand overnight. Water was added to dissolvethe precipitated piperidine hydrochloride salt. The organic layer wasthen washed sequentially with 5% hydrochloric acid and sodiumbicarbonate solutions and finally with a saturated salt solution untilthe wash was neutral to litmus paper and dried over anhydrous magnesiumsulfate. After filtering, the solvent was removed under reduced pressure(water pump). The crude amide was distilled under high vacuum to give31.4 grams of product--b.p. 114°-15° C./0.2 mm Hg), n_(D) ²⁵ 1.5159.

The physical constants of the compounds are presented in Table 1.

The repellent activity of the amides of the present invention wasdemonstrated by practical laboratory and field tests against mosquitoesand a variety of other biting diptera. The effectiveness of therepellents was determined by directly comparing their repellency withthat of deet in tests on skin and with dimethyl phthalate in tests oncloth.

In the following description of the testing procedures the firstconfirmed bite is defined as a bite followed by another within thirtyminutes.

For the purposes of this invention, the compounds were tested as solutesin alcohol, acetone, or other volatile solvent. However, othercompatible liquid or solid carriers may also be used.

TESTING PROCEDURES Stable Flies

The repellents were applied as 1-ml aliquots of a 25% ethanol solutionand spread evenly over the forearm of a subject from wrist to elbow.Since the ethanol solution was formulated on a weight-volume basis, 250mg of repellent was applied to the forearm in each test. The mostpromising compounds (those equal to or better than the deet standard atthe 25% dosage) were then tested as 12.5% and 6.25% ethanol solutions.

The evaluations were carried out in an outdoor cage (103 cm square and133 cm high) constructed of aluminum and having a solid top and bottomand screen wire on four sides. Four of the sides had port openingscovered with 30.5-cm (12-in.) tubular cloth stockinettes. The centers ofthe ports were 30 cm from the bottom of the cage, which rested on atable 80 cm high. One arm each of up to four treated subjects at a timecould be inserted through the ports into the cage.

Approximately 12,000 S. calcitrans pupae were placed in cups and allowedto emerge in the test cage over an 8-day period. The tests were startedthe 4th day, when approximately 8000 flies had emerged. The remaining4000 that emerged over the next 4 days maintained a relatively stablepopulation in respect to numbers and avidity. Citrated beef blood on acotton pad was offered for 45 minutes each day after the repellent testswere completed. This short-term feeding period provided a small butadequate food intake, and avidity was not reduced as a result ofcomplete engorgement. Results obtained when an untreated forearm wasinserted into the test cage before and during the tests each day gave ameasure of the avidity of the flies, though it was impossible to countthe attacks on the untreated arm.

The effectiveness of each chemical was determined by the protectiontime; that is, the time between treatment and the first confirmed bite.Therefore, 30 minutes after the application of the test chemical andevery 30 minutes thereafter, the treated arms were inserted into thetest cage for 3 minutes unless bites occurred sooner.

Since test subjects differ in attractiveness and insects differ inavidity, the best measure of the effectiveness of a repellent is itsratio of protection time vs. that of a standard repellent used insimilar conditions. Deet was the standard in all of the tests reportedhere. It was paired with each of the other candidate repellents in 10different test series.

The experimental design used was a round-robin series in which eachrepellent was paired concurrently against another repellent on the armsof a subject. An adjusted average protection time that allowed forindividual variation between test subjects and test conditions was thencomputed (Soap and Chemical Specialties, 33, 115-17 and 129-133, 1957).

Black Flies

The principal test site was in the vicinity of Kidney Pond, Baxter StatePark, Maine. Meadows bordered by fast moving mounting streams and anabundance of wildlife provided optimum breeding conditions in this area.Several species of blackflies were represented in the populationattacking four test subjects. Of these, the two most abundant wereidentified as Simulium venustum Say and Prosimulium mixtum Syme andDavis. Repellents were applied as 1-ml aliquots of a 12.5 or 25% ethanolsolution and spread evenly over the forearm of a subject from wrist toelbow. The ethanol solution was formulated on a weight-volume basis, soeither 125 or 250 mg of repellent was applied in each test.

Treated arms were continuously exposed to the natural populations offlies. Subjects intermittently moved about with arms raised or on hips,squatted, or sat down for brief periods of 5 to 10 minutes. Thesepositions, coupled with slow walking and standing every few minutes,appeared to be attractive to black flies (Simulids and Prosimulids) andwere used as standard procedure in all tests. Head-nets and gloves wereworn by the test subjects to prevent attack on exposed untreated partsof the body.

Two series of round-robin tests were conducted in the spring of 1977using 12.5 or 25% solutions of repellent in ethanol; one series wasconducted during June 1978 using a 25% solution of repellent in ethanol.The effectiveness of each chemical was determined by the protectiontime, i.e., the time between treatment and the first confirmed bite.Since test subjects differ in attractiveness and insects differ inavidity, the best measure of the effectiveness of a repellent is theratio of its protection time to that of a standard repellent undersimilar conditions. Deet was the standard repellent in these tests.

In the round-robin test each repellent was paired with each otherrepellent on the arms of a subject (four or five replicates). Anadjusted average protection time that allowed for individual variationsbetween test subjects and test conditions was then computed. Black flylanding rates ranged from 14 to 40/minute during the test period.

Deer Flies

The compounds and the standard repellent, deet, were tested on theforearms of human subjects against natural populations of the deer fly,Chrysops atlanticus. The materials were formulated as 25% ethanolsolutions and applied at the rate of 1 ml per forearm. The field testswere conducted along logging roads adjacent to the marshes of theOgeechee River at Richmond Hill, Ga., where C. atlanticus populationsoccur in great numbers annually. Since the flies are attracted tomotion, the test subjects continually walked while exposing theirtreated arms to the flies. The tests were terminated when a confirmedbite was received. The chemicals were evaluated in round-robin testswith five compounds and a deet standard in each series. During the3-week test period the landing rate averaged 33 flies/man and rangedfrom 13 to 54/man.

Sand Flies

Two test sites were used, one at YankeeTown, Fla. on the Gulf coast andone at Parris Island, S.C. The repellents were applied as 25% solutionsin ethanol on the forearms (wrist to elbow) of test subjects. Because ofthe limited period of insect activity (early morning or late afternoonto dusk) the subjects were pretreated 2 hours prior to the test periodto effect aging of the repellents. The repellents were evaluated againstthe standard repellent, deet, in paired tests (3 replications). A testrepellent was applied to one arm of a subject and deet to the other.Effectiveness were determined by the number of bites received during thetest period. A control (no repellent treatment) was included in eachtest to ascertain the level of insect pressure.

Mosquitoes

Tests on skin.

For laboratory tests, 1 ml of a 25% ethanol solution of the repellentwas spread evenly over the forearm of the subject. The treated forearmswere exposed to about 1500 female laboratory reared Aedes aegypti orAnopheles quadrimaculatus mosquitoes in cages. Effectiveness was basedon complete protection, that is, the time between treatment and thefirst confirmed bite. The effectiveness of the compounds was compared tothat of the standard repellent, deet. The chemicals were tested in around-robin series in a balanced incomplete block design in which eachrepellent in the series was paired against each other repellent in theseries on opposite arms of a given number of subjects.

The field tests were conducted at sites adjacent to Mosquito Lagoon nearNew Smyrna Beach, Fla. The repellents were applied in the same manner asfor the laboratory tests. The treated arms were exposed continuously tothe natural population of mosquitoes until the first confirmed bite wasreceived. Protection clothing and head nets were worn by the testsubjects to protect against attack on exposed untreated parts of thebody. The experimental design used was a balanced incomplete block as inthe laboratory tests.

Tests on cloth.

Test materials were applied at the rate of 3.3 g of compound per 0.1 m²cloth to a measured portion (0.03 m²) of a cotton stocking as 10%solutions in acetone or other volatile solvent. After 2 hours, thetreated stocking was placed over an untreated nylon stocking on the armof a human subject and exposed for 1 minute in a cage containing about1500 five- to eight-day old A. aegypti or A. quadrimaculatus. The testexposure was repeated at 24 hours and then at weekly intervals untilfive bites were received in 1 minute. Days to the first bite and to fivebites were recorded. Between tests, the treated stockings were placed ona rack at room temperature, and evaporation was allowed to continue. Astandard repellent, dimethyl phthalate, was tested concurrently and waseffective for 11 to 21 days against both mosquito species.

The merits of the present invention are illustrated in the results shownin the tables.

The data in Table 2 show compounds 2, 7, 20, 33, 34, 47, and 49 weremore active against the stable fly than the deet standard at allconcentrations tested. Compounds 20 and 34 were significantly moreeffective than deet at all three dosages (0.05% level of confidence).Compounds 21 and 35 were more active than deet at two concentrations andequal to it at the lowest concentration tested. The repellent effect ofcertain of these chemicals was as much as 4.5× that of deet and providedprotection up to 9 hours; the protection time of deet ranged from 2 to 3hours. Data for compounds 4, 6, 17, 18, 19, 31, and 45 are shown toillustrate the unpredictability of repellent activity of closely relatedchemicals.

The data in Table 3 show all eight compounds and deet are very goodblack fly repellents. Compound 21 is significantly more effective thandeet at the 25% dosage providing about 10.5 hours protection. There isno significant difference between the remaining compounds and deet atthe 25% dosage. Although not significantly more effective than deet, theadjusted mean for compound 20 was 0.5 and 1.5 hours greater than that ofdeet at the two test dosages. Compounds 7 and 35 provided about 7 hoursprotection; compounds 20 and 47 provided over 8 hours protection;compounds 6 and 33 provided about 9 hours protection.

The data in Table 4 show 10 compounds that exceeded deet in repellencyagainst deer flies. Compound 20 was significantly more effective thandeet with an adjusted mean protection time of 6.3 hours.

The data in Table 5 show compounds 2, 7, 20, and 35 greatly superior todeet in tests conducted in Florida against the sand fly Culicoidesmississippiensis. Compounds 2 and 20 were also superior to deet in theParris Island tests against Culicoides hollensis. Deet is considered agood repellent for sand flies (Meditsinskaya Parazitologiya iParazitarnye Bolezni, 35 (5), 549, 1963). A biting rate of about 5/hourwould make the presence of sand flies tolerable to most people (Journalof Economic Entomology, 64 (1), 264, 1971). The data show certaincompounds of this invention equalling or exceeding this criteria in onetest and equalling or closely approaching it in the second test. Thenumber of bites experienced by the check, clearly shows very high insectpressure during these tests, emphasizing the effectiveness of therepellents.

The data in Table 6 show the relative repellency of compounds of thisinvention against mosquitoes when applied to skin in laboratory andfield tests. Deet is an excellent mosquito repellent (The Journal of theAmerican Medical Association, 196, 253, 1966). Repellents 33 and 34 wereabout equally as effective against Aedes aegypti as deet; repellents 19,20, 21, and 34 were about equally as effective against Anophelesquadrimaculatus as deet. In field tests, repellents 2 and 20 were 1.5and 1.4 times as effective as deet against Aedes taeniorhynchus and 4,6, 7, 21, 33, and 47 were about equally as effective as deet. Becausedeet is such an effective mosquito repellent, chemicals having 0.5ratios to deet are considered good mosquito repellents.

The data in Table 7 show 91 of the repellents were more effective thanthe standard against one species of mosquito and 9 other compounds wereabout equally as effective as the standard. Repellents 91, 100, 101, and115 provided outstanding protection of over 200 days and 29 otherrepellents provided exceptional protection of over 100 days against onespecies or the other. All chemicals providing 11 or more days protectionare considered promising repellents.

The foregoing examples of repellent action of these novel amides againstspecific insect pests is meant to be illustrative rather than limiting.For example, the compounds of the present invention can be mixed withinert ingredients or with other known insect repellents. The compoundsmay also be formulated or embodied into repellent compositions in theform of creams, lotions, emulsions, suspensions, solutions, dusts, andaerosol or other type of sprays.

Although insect repellents are usually applied to the skin, thecompounds of this invention and formulations containing them are alsouseful when applied to clothing, netting, packaging, shippingcontainers, animals, and growing plants.

                  TABLE 1                                                         ______________________________________                                        Physical constants of compounds synthesized in accordance with                the procedures of this invention                                               No.                                                                                 ##STR3##          or m.p. (°C.)B.p. (°C./mmHg)Physica                            l constants   n.sub.D.sup.25                          ______________________________________                                         ##STR4##                                                                     1     N,NDimethylamino  69-70/0.45   1.4794                                   2     N,NDipropylamino  93-5/0.45    1.4685                                   3     N,NDibutylamino   133/1.5      1.4675                                   4     1-Pyrrolidyl      67-8                                                  5     1-Piperidyl       108/0.45     1.5030                                   6     1-Hexahydro-1Hazepinyl                                                                          120/0.25     1.5038                                   7     2-Methyl-1-piperidyl                                                                            110-13/0.7   1.5001                                   8     3-Methyl-1-piperidyl                                                                            114-16/0.45  1.4974                                   9     4-Methyl-1-piperidyl                                                                            113-14/0.8   1.4970                                   10    2-Ethyl-1-piperidyl                                                                             131/1.5      1.4970                                   11    2,6-Dimethyl-1-piperidyl                                                                        109-11/0.5   1.4950                                   12    1,2,3,6-Tetrahydro-1-                                                                           107-9/0.5    1.5175                                         pyridinyl                                                               13    4-Methyl-1-piperazinyl                                                                          100-2/0.1    1.5041                                   14    4-Morpholinyl     57-8                                                  15    2,6-Dimethyl-4-morpholinyl                                                                      116-17/0.3   1.4919                                    ##STR5##                                                                     16    N,NDimethylamino  75-6/0.4     1.4960                                   17    N,NDipropylamino  88/0.15      1.4804                                   18    N,NDibutylamino   103/0.1      1.4775                                   19    1-Pyrrolidyl      44-5                                                  20    1-Piperidyl       114-15/0.2   1.5159                                   21    1-Hexahydro-1Hazepinyl                                                                          105-6/0.15   1.5151                                   22    2-Methyl-1-piperidyl                                                                            110-12/0.1   1.5106                                   23    3-Methyl-1-piperidyl                                                                            108-10/0.1   1.5087                                   24    4-Methyl-1-piperidyl                                                                            110-12/0.15  1.5087                                   25    2-Ethyl-1-piperidyl                                                                             114-15/0.1   1.5068                                   26    2,6-Dimethyl-1-piperidyl                                                                        112-13/0.1   1.5055                                   27    1,2,3,6-Tetrahydro-1-                                                                           114-16/0.45  1.5315                                         pyridinyl                                                               28    4-Methyl-1-piperazinyl                                                                          112-14/0.1   1.5181                                   29    4-Morpholinyl     114-16/0.25  1.5194                                   30    2,6-Dimethyl-4-morpholinyl                                                                      115-16/0.4   1.5043                                    ##STR6##                                                                     31    N,NDipropylamino  100/0.7      1.4682                                   32    N,NDibutylamino   126/0.9      1.4669                                   33    1-Pyrrolidyl      95/0.25      1.4941                                   34    1-Piperidyl       104-6/0.5    1.4970                                   35    1-Hexahydro-1Hazepinyl                                                                          115-18/0.9   1.5000                                   36    2-Methyl-1-piperidyl                                                                            141-3/0.25   1.4930                                   37    3-Methyl-1-piperidyl                                                                            168-70/18    1.4909                                   38    4-Methyl-1-piperidyl                                                                            108/0.8      1.4908                                   39    2-Ethyl-1-piperidyl                                                                             175-8/18     1.4930                                   40    2,6-Dimethyl-1-piperidyl                                                                        108-10/0.5   1.4905                                   41    1,2,3,6-Tetrahydro-1-                                                                           118-20/1.3   1.5100                                         pyridinyl                                                               42    4-Methyl-1-piperazinyl                                                                          120-2/1.0    1.4990                                   43    4-Morpholinyl     108-9/0.4    1.4975                                   44    2,6-Dimethyl-4-morpholinyl                                                                      75-7                                                   ##STR7##                                                                     45    N,NDipropylamino  108/2.0      1.4794                                   46    N,NDibutylamino   120/0.45     1.4765                                   47    1-Pyrrolidyl      133-6/0.2    1.5082                                   48    1-Piperidyl       109/0.5      1.5090                                   49    1-Hexahydro-1Hazepinyl                                                                          135/0.9      1.5116                                   50    2-Methyl-1-piperidyl                                                                            120-2/1.1    1.5049                                   51    3-Methyl-1-piperidyl                                                                            120-2/1.3    1.5035                                   52    4-Methyl-1-piperidyl                                                                            122-4/1.0    1.5020                                   53    2-Ethyl-1-piperidyl                                                                             116-18/0.5   1.5036                                   54    2,6-Dimethyl-1-piperidyl                                                                        115-17/0.5   1.5017                                   55    1,2,3,6-Tetrahydro-1-                                                                           113-15/0.7   1.5234                                         pyridinyl                                                               56    4-Methyl-1-piperazinyl                                                                          105-7/0.3    1.5106                                   57    4-Morpholinyl     104-5/0.2    1.5115                                   58    2,6-Dimethyl-4-morpholinyl                                                                      122-5/0.4    1.4990                                    ##STR8##                                                                     59    N,NDipropylamino  93-5/0.2     1.4900                                   60    N,NDibutylamino   100-2/0.1    1.4862                                   61    1-Pyrrolidyl      105-8/0.15   1.5262                                   62    1-Piperidyl       111-13/0.2   1.5244                                   63    1-Hexahydro-1Hazepinyl                                                                          121-2/0.4    1.5262                                   64    2-Methyl-1-piperidyl                                                                            108-9/0.2    1.5197                                   65    3-Methyl-1-piperidyl                                                                            110-12/0.3   1.5169                                   66    4-Methyl-1-piperidyl                                                                            98-100/0.1   1.5163                                   67    2-Ethyl-1-piperidyl                                                                             108-9/0.15   1.5168                                   68    2,6-Dimethyl-1-piperidyl                                                                        100-1/0.15   1.5166                                   69    1,2,3,6-Tetrahydro-1-                                                                           110/0.1      1.5401                                         pyridinyl                                                               70    4-Methyl-1-piperazinyl                                                                          103-4/0.1    1.5253                                   71    4-Morpholinyl     99-100/0.1   1.5258                                   72    2,6-Dimethyl-4-morpholinyl                                                                      100-2/0.1    1.5113                                    ##STR9##                                                                     73    N,NDimethylamino  87-8/0.45    1.4780                                   74    N,NDipropylamino  108-9/0.45   1.4708                                   75    N,NDibutylamino   139/0.75     1.4698                                   76    1-Pyrrolidyl      110-12/0.25  1.4977                                   77    1-Piperidyl       109-11/0.2   1.5000                                   78    1-Hexahydro-1Hazepinyl                                                                          114-16/0.2   1.5019                                   79    2-Methyl-1-piperidyl                                                                            105-7/0.2    1.4945                                   80    3-Methyl-1-piperidyl                                                                            118/0.4      1.4942                                   81    4-Methyl-1-piperidyl                                                                            121/0.5      1.4935                                   82    2-Ethyl-1-piperidyl                                                                             122-4/0.2    1.4943                                   83    2,6-Dimethyl-1-piperidyl                                                                        121-3/0.3    1.4942                                   84    1,2,3,6-Tetrahydro-1-                                                                           122-4/0.15   1.5114                                         pyridinyl                                                               85    4-Methyl-1-piperazinyl                                                                          109/0.15     1.5016                                   86    4-Morpholinyl     68-70                                                 87    2,6-Dimethyl-4-morpholinyl                                                                      125-7/0.5    1.4892                                    ##STR10##                                                                    88    N,NDimethylamino  100-2/0.4    1.4782                                   89    N,NDipropylamino  117-18/0.45  1.4715                                   90    N,NDibutylamino   133-5/0.4    1.4701                                   91    1-Pyrrolidyl      126-7/0.2    1.4928                                   92    1-Piperidyl       129-31/0.2   1.4950                                   93    1-Hexahydro-1Hazepinyl                                                                          131-4/0.3    1.4985                                   94    2-Methyl-1-piperidyl                                                                            128-30/0.35  1.4933                                   95    3-Methyl-1-piperidyl                                                                            136-8/0.5    1.4912                                   96    4-Methyl-1-piperidyl                                                                            136-7/0.5    1.4919                                   97    2-Ethyl-1-piperidyl                                                                             126-7/0.1    1.4938                                   98    2,6-Dimethyl-1-piperidyl                                                                        135/0.35     1.4895                                   99    1,2,3,6-Tetrahydro-1-                                                                           134-5/0.5    1.5070                                         pyridinyl                                                               100   4-Methyl-1-piperazinyl                                                                          139-40/0.1   1.4966                                   101   4-Morpholinyl     122-4/0.1    1.4961                                   102   2,6-Dimethyl-4-morpholinyl                                                                      123-5/0.1    1.4876                                    ##STR11##                                                                    103   N,NDimethylamino  109-10/0.4   1.4764                                   104   N,NDipropylamino  128-30/0.4   1.4712                                   105   N,NDibutylamino   148/0.4      1.4705                                   106   1-Pyrrolidyl      137-9/0.4    1.4905                                   107   1-Piperidyl       139-40/0.5   1.4920                                   108   1-Hexahydro-1Hazepinyl                                                                          153-4/0.5    1.4940                                   109   2-Methyl-1-piperidyl                                                                            142-3/0.45   1.4909                                   110   3-Methyl-1-piperidyl                                                                            143-5/0.5    1.4882                                   111   4-Methyl-1-piperidyl                                                                            145-7/0.45   1.4875                                   112   2-Ethyl-1-piperidyl                                                                             145/0.25     1.4910                                   113   2,6-Dimethyl-1-piperidyl                                                                        151-3/0.5    1.4874                                   114   1,2,3,6-Tetrahydro-1-                                                                           145-6/0.45   1.5035                                         pyridinyl                                                               115   4-Methyl-1-piperazinyl                                                                          134-5/0.15   1.4975                                   116   4-Morpholinyl     149-51/0.45  1.4932                                   117   2,6-Dimethyl-4-morpholinyl                                                                      145-7/0.45   1.4828                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Repellency of compounds to the stable fly Stomoxyx                            calcitrans when applied to the skin at various concentrations                 in ethanol and compared to deet as a test standard                                     Protection time                                                               (minutes)                                                                  %                  Adjusted                                                                             Ratio to                                                                              No. of                                No.   Conc.    Range     mean   deet.sup.a                                                                            tests                                 ______________________________________                                         2    6.25     30-90      55    1.7     3                                           12.5     300-360   315    4.50.sup.b                                                                            5                                           25.0     210-463   321    2.02.sup.b                                                                            5                                      4    25.0      30-270   103    0.4     5                                      6    25.0      30-268   183    0.71    5                                      7    25.0     120-300   246    2.01.sup.b                                                                            4                                     17    25.0     180-360   225    0.85    5                                     18    25.0      30-189   122    0.46    5                                     19    25.0      90-420   237    1.0     5                                     20    6.25      30-120   103    2.5.sup.b                                                                             3                                           12.5      60-240   128    2.4.sup.b                                                                             4                                           25.0     360-390   387    2.39    5                                     21    6.25     30-60      33    1.0     5                                           12.5     270-450   306    1.42    5                                           25.0     300-510   457    3.78.sup.b                                                                            4                                     31    25.0     30-60      36    0.2     5                                     33    6.25      60-180   80     1.6     3                                           12.5      90-210   150    3.3.sup.b                                                                             4                                           25.0     240-270   266    1.6     4                                     34    6.25      30-120   118    2.4.sup.b                                                                             3                                           12.5     270-330   320    4.57.sup.b                                                                            5                                           25.0     390-510   419    2.6.sup.b                                                                             4                                     35    6.25     30-30      30    1.0     5                                           12.5     210-375   326    3.27.sup.b                                                                            5                                           25.0     390-510   459    2.9.sup.b                                                                             4                                     36    25.0      30-120   101    1.43    5                                     45    25.0      30-180    78    0.44    5                                     47    6.25     30-90      63    1.9     3                                           12.5     120-270   230    3.29.sup.b                                                                            5                                           25.0     150-405   264    1.66    5                                     49    6.25     30-60      38    1.15    5                                           12.5     150-330   306    1.42    5                                           25.0     480-510   538    3.02.sup.b                                                                            5                                     50    25.0      60-150   125    1.41    5                                     ______________________________________                                         .sup.a Data compiled from a number of different tests, accounting for the     fluctuation between protection time and ratio to deet amoung the members      of the series.                                                                .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 3                                                         ______________________________________                                        Repellency of compounds applied to the skin as 12.5 and/or                    25% ethanol solutions compared with deet against                              blackflies in two series of field tests                                                                             No.                                     %           Protection time (min)                                                                          Ratio to of                                      No.     Conc.   Range    Adjusted mean                                                                           deet   tests                               ______________________________________                                        Test I (1977)                                                                 Deet (Std)                                                                            12.5    145-283  161       1.00   5                                           25.0    287-511  426       1.00   4                                   20      12.5    123-314  193       1.20.sup.a                                                                           5                                           25.0    413-565  505       1.19.sup.a                                                                           4                                    7      12.5     26-222   95       0.59   5                                           25.0    309-515  424       1.00.sup.a                                                                           4                                   35      12.5     24-126   93       0.58   5                                           25.0    342-542  412       0.97.sup.a                                                                           4                                    2      12.5     25-112   71       0.44   5                                           25.0    198-375  314       0.74.sup.a                                                                           4                                   Test II (1978)                                                                Deet (Std)                                                                            25.0    399-623  520       1.00   5                                    6      25.0    411-628  537       1.03.sup.a                                                                           5                                   21      25.0    524-725  632       1.21.sup.b                                                                           5                                   33      25.0    498-603  554       1.07.sup. a                                                                          5                                   47      25.0    425-649  486       0.94.sup.a                                                                           5                                   ______________________________________                                         .sup.a Not significantly different from deet at the 0.05% level of            confidence.                                                                   .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 4                                                         ______________________________________                                        Repellency of compounds applied to the skin as                                25% ethanol solutions and compared with deet against                          deerflies in field tests (Avg. of 5 tests)                                    Protection time (min)   Ratio to                                              No.    Range        Adjusted mean                                                                             deet.sup.a                                    ______________________________________                                         2      10-178      133         3.00                                           4      4-77        23          0.51                                           6      10-173      75          1.69                                          17      15-143      62          1.39                                          18      6-36        40          0.89                                          20     363-421      380         .sup. 5.83.sup.b                              21      91-203      91          1.1                                           31     10-44        45          0.62                                          34      20-408      141         1.8                                           35      42-182      119         1.5                                           36      5-17        15          0.94                                          45      4-110       18          0.24                                          47      40-160      138         1.89                                          49      37-244      129         1.76                                          50      8-138       27          1.11                                          ______________________________________                                         .sup.a Data compiled from a number of tests, accounting for the               fluctuation between the protection time and ratio to deet amoung the          members of the series.                                                        .sup.b Significantly different from deet at the 0.05% level of confidence

                  TABLE 5                                                         ______________________________________                                        Repellency of compounds applied to the skin                                   as 25% ethanol solutions and compared with deet                               against the sandflies Culicoides mississippiensis                             and Culicoides hollensis in field tests                                       Compounds      Average  Average                                               paired         bites/test                                                                             bites/hour                                            ______________________________________                                        Tests at Yankee Town, Fla. (Avg. 3 tests)                                     Deet           29.0     19.2                                                   2             3.33     2.4                                                   Deet           31.67    21.0                                                  20             5.0      3.6                                                   Deet           106.0    70.8                                                  35             6.67     4.2                                                   Deet           45.0     30.0                                                   7             10.0     6.6                                                   Check          1299     865.8                                                 Tests at Parris Island, S.C. (Avg. 3 tests)                                   Deet           28.67    18.6                                                  20             9.33     6.0                                                   Deet           85.0     54.6                                                   2             16.33    10.8                                                  Deet           12.0     7.8                                                    7             16.67    10.8                                                  Check          1566     1277.4                                                ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Repellency of compounds to mosquitoes when applied                            to the skin as 25% ethanol solutions                                          Ratio to deet                                                                 Laboratory test        Field test                                                    Aedes       Anopheles   Aedes                                          No.    aegypti     quadrimaculatus                                                                           taeniorhynchus                                 ______________________________________                                         2     0.22        0.28        1.5                                             4     0.22        0.11        0.77                                            6     0.14        0.74        0.82                                            7     0.70        0.11        1.15                                           17     0.24        0.33        0.52                                           18     0.13        0.05        0.07                                           19     0.20        0.73        0.44                                           20     0.68        1.0         1.4                                            21     0.64        0.86        0.7                                            31     0.24        0.08        0.45                                           33     1.12        0.86        0.69                                           34     0.89        1.0         0.34                                           45     0.23        0.11        0.12                                           47     0.28        0.24        0.99                                           49     0.55        0.09        0.65                                           ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Repellency of compounds to mosquitoes in tests on cloth.                             Aedes aegypti Anopheles quadrimaculatus                                       Days to       Days to                                                  No.      1st bite                                                                              5 bites     1st bite                                                                            5 bites                                    ______________________________________                                         2       15      15           8     8                                          4       30      38          38    79                                          5       30      38          30    30                                          6       106     113         22    38                                          7       104     104         111   111                                         8       104     104         22    22                                          9       52      104          0    22                                         10       104     104          1    22                                         11       104     104          1    37                                         12       15      15          15    15                                         13        7      15           7    111                                        14        0       1          27    27                                         15       15      28          35    35                                         17       15      15          15    15                                         18        0      30           0     1                                         19       28      28          70    94                                         20       21      28          28    48                                         21       64      87          70    70                                         22       69      69          83    83                                         23       36      36          36    51                                         24       20      20          83    83                                         25       83      83          83    83                                         26       36      36          36    36                                         27       36      36          63    63                                         28       28      28          63    83                                         29        0       0          35    35                                         30        8       8          22    22                                         31       15      15           1     1                                         33       21      28          28    28                                         34       21      28          13    13                                         35       28      28           6     6                                         36       23      43           0     0                                         37       23      51           0     0                                         38       36      36          21    21                                         39       51      71           0     0                                         40        1      23           0     0                                         41        8      15           8     8                                         42        1       1          36    50                                         43       36      77          64    71                                         44       28      28          15    15                                         45       27      27           1     1                                         47       27      27           1     1                                         48       33      41           1     1                                         49       27      47           1     1                                         50       23      51           0    23                                         51       36      36           0    21                                         52       36      36           8    36                                         55       15      15           0     1                                         57        8      22          36    105                                        58        1      28          22    22                                         59        1      35          49    49                                         61       34      55          28    28                                         62       70      70          70    91                                         63       70      128          0    111                                        64       70      70           0    76                                         65       35      70           0    49                                         66       70      70           0    77                                         67       21      34          47    47                                         68        1      28          20    20                                         69       28      28          20    20                                         70       28      28          47    47                                         71        0       0          47    47                                         72        0      34          20    190                                        74        0       0          28    28                                         76       108     108         21    119                                        77       28      108         28    28                                         78       21      130          1     8                                         79       28      102          0     0                                         80       28      102          0     0                                         81       28      51           8     8                                         82        0      28           8     8                                         83       101     108         108   108                                        84        8      28          28    28                                         85        0      105         134   175                                        86        0      1            1    18                                         87        0      105         126   126                                        88       21      21          24    24                                         91       169     169         238   238                                        92       29      29           7    182                                        93       21      65          21    44                                         94        7      21           1     1                                         95        7      21           1    126                                        97        0      12           0    12                                         98        0      21          126   126                                        99        0      12           0    93                                         100       7       7          21    268                                        101      61      133         238   238                                        102      61      93          133   133                                        103      42      42          24    54                                         106      61      160         160   160                                        107       0      36          36    36                                         108      22      22          36    134                                        110       0       1          36    36                                         111       0       0          52    94                                         112      13      13          36    104                                        113       0       1          134   134                                        114       0      36          134   134                                        115       0      51          310    318+                                      116      77      134         134   134                                        117      22      22          134   134                                        ______________________________________                                         + Compound still in test.                                                

We claim:
 1. A method of repelling stable flies, blackflies, deerflies, sand flies and mosquitoes comprising applying to the skin an effective repellent amount of a compound of the formula ##STR12## wherein R³ is ##STR13## and R is hydrogen.
 2. The method of claim 1 wherein the compounds are applied to the skin in an ethanol solution containing from 6.25% to 25%, w/v, of the compound. 